Advanced Pharmacology · Topic 8 of 13

Anticoagulants: Heparins, Warfarin & DOACs

Pharmacology · anticoagulation

Anticoagulants: Heparins, Warfarin & DOACs

Heparins work through antithrombin, warfarin starves the vitamin K–dependent factors, and DOACs block Xa or thrombin directly — choose by indication, kidneys and need for speed.

Key numbers

IV heparin 80 units/kg, then 18 units/kg/haPTT 1.5–2.5 × control

Enoxaparin 1 mg/kg every 12 hours1 mg/kg q12h

Warfarin INR 2.0–3.0INR 2.0–3.0

CrCl under 30: unfractionated heparin or warfarinCrCl < 30 mL/min

01 · GiveIV heparin 80 units/kg, then 18 units/kg/h

Weight-based IV unfractionated heparin for VTE: 80 units/kg bolus, then 18 units/kg/h, titrated to an aPTT 1.5–2.5 times control (or anti-Xa 0.3–0.7 IU/mL).

02 · WatchWarfarin INR 2.0–3.0

Warfarin's usual INR target is 2.0–3.0. Start it with a heparin and overlap at least 5 days and until the INR is in range for 24 hours, because its full effect takes several days.

03 · The ruleDOACs first, except valves, APS, pregnancy

DOACs are preferred over warfarin for VTE and nonvalvular AF, but are not used with a mechanical heart valve, moderate-to-severe rheumatic mitral stenosis, antiphospholipid syndrome or pregnancy.

What it is

Core idea

Heparins act through antithrombinUnfractionated heparin activates antithrombin against thrombin and factor Xa; LMWH acts mainly on Xa; fondaparinux only on Xa. DOACs act directly — dabigatran on thrombin, the -xabans on Xa.

Warfarin blocks vitamin K recycling (VKORC1)Warfarin inhibits vitamin K epoxide reductase (VKORC1), lowering factors II, VII, IX and X and proteins C and S; anticoagulation begins within 24 hours but peaks at 72–96 hours.

Diagnosis & monitoring

Work-up

Check platelets on any heparinCheck platelet counts during unfractionated heparin or LMWH: HIT is far more common with unfractionated heparin; long-term unfractionated heparin also causes hyperkalemia, raised liver enzymes and osteopenia.

Management

Orders

Enoxaparin 1 mg/kg every 12 hours must knowTreatment-dose enoxaparin is 1 mg/kg subcutaneously every 12 hours or 1.5 mg/kg once daily; it needs no routine monitoring and causes HIT less often than unfractionated heparin.

Apixaban 5 mg twice daily for AFApixaban for AF is 5 mg twice daily, reduced to 2.5 mg twice daily with any 2 of: age ≥ 80, weight ≤ 60 kg, creatinine ≥ 1.5 mg/dL.

Rivaroxaban: take with foodRivaroxaban for AF is 20 mg once daily with the evening meal (15 mg if CrCl ≤ 50 mL/min); for VTE, 15 mg twice daily for 21 days, then 20 mg daily, always with food.

Dabigatran: 80% renal, dialyzable thrombin inhibitorDabigatran, a direct thrombin inhibitor, is 80% renally cleared and removable by dialysis: 150 mg twice daily for AF (75 mg if CrCl 15–30), and for VTE only after 5–10 days of parenteral anticoagulation.

Hold apixaban 48 hours; usually no bridgingBefore high-bleeding-risk procedures stop apixaban ≥ 48 hours (24 if low risk) and dabigatran 1–2 days (3–5 if CrCl < 50); DOACs need no bridging, and warfarin is bridged only at high thrombotic risk.

Reversal: protamine, vitamin K + PCC, idarucizumabReversal: protamine for heparin (partial for LMWH), IV vitamin K plus 4-factor PCC for warfarin, idarucizumab for dabigatran, and 4-factor PCC for factor Xa inhibitors since andexanet's December 2025 US withdrawal.

Fondaparinux 7.5 mg daily, weight-bandedFondaparinux (Xa inhibition via antithrombin) treats VTE at 7.5 mg subcutaneously daily (5 mg if < 50 kg, 10 mg if > 100 kg); it rarely causes thrombocytopenia but is contraindicated with CrCl < 30.

Red flags & don'ts

Avoid harm

CYP2C9 inhibitors raise the INR interactionWarfarin is cleared mainly by CYP2C9: amiodarone, fluconazole, metronidazole and trimethoprim-sulfamethoxazole raise the INR; rifampin, carbamazepine and phenobarbital lower it. Recheck the INR whenever any drug starts or stops.

Early warfarin is procoagulant: skin necrosis complicationProtein C falls faster than most clotting factors, so early warfarin without heparin is transiently procoagulant and can cause skin necrosis — especially with protein C or S deficiency or untreated HIT.

Avoid DOACs with rifampin, carbamazepine, phenytoin interactionAvoid apixaban and rivaroxaban with combined P-gp and strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St John's wort); halve apixaban with combined strong inhibitors such as ketoconazole, itraconazole or ritonavir.

The rules

Know these

CrCl under 30: unfractionated heparin or warfarin must knowWith CrCl under 30 mL/min, unfractionated heparin (not renally cleared) or warfarin are the usual choices; reduce treatment enoxaparin to 1 mg/kg once daily, and avoid fondaparinux and, for VTE, apixaban, rivaroxaban and dabigatran.

Warfarin to DOAC: start when INR fallsSwitching from warfarin: stop it and start apixaban or dabigatran when the INR is below 2.0, edoxaban at ≤ 2.5, or rivaroxaban below 3.0.

Warfarin or a DOAC?

Commonly confused

Target	Vitamin K–dependent factors II, VII, IX, X and proteins C and S
Monitoring	INR, usually 2.0–3.0
Onset	Peak at 72–96 h — overlap with heparin ≥ 5 days
Choose it for	Mechanical valve, rheumatic mitral stenosis, antiphospholipid syndrome
Interactions	CYP2C9 drugs, dietary vitamin K

Teach & follow up

Patient education

Keep dietary vitamin K consistentTeach patients on warfarin to eat a normal diet with a consistent amount of vitamin K — avoiding drastic changes such as suddenly eating large amounts of green leafy vegetables — rather than eliminating it.

More detail

Reference

Show 9 reference facts

Edoxaban 60 mg daily (30 mg for CrCl 15–50, weight ≤ 60 kg or certain P-gp inhibitors) follows 5–10 days of parenteral therapy for VTE; in AF, avoid it when CrCl exceeds 95.

From LMWH or a non-warfarin anticoagulant, start the DOAC when the next dose is due; apixaban and rivaroxaban need no heparin lead-in, but dabigatran and edoxaban follow at least 5 days of parenteral therapy.

DOACs raise the INR, so when switching to warfarin, stop the DOAC and start a parenteral anticoagulant plus warfarin at the next DOAC dose time, stopping the parenteral drug once the INR is in range.

During PCI, unfractionated heparin is titrated to an activated clotting time of 250–300 seconds (200–250 seconds with a GP IIb/IIIa inhibitor); outside the cath lab, aPTT-guided dose changes are made about every 6 hours.

Anti-Xa levels can monitor LMWH in renal impairment, pregnancy with a mechanical valve, or unexpected bleeding; LMWH barely changes the aPTT.

Warfarin usually starts at 2–5 mg daily, lower in older adults and liver disease; CYP2C9 and VKORC1 variants change the dose needed, and the effective half-life averages about 40 hours.

Warfarin is teratogenic and contraindicated in pregnancy except with a mechanical heart valve; DOACs are not used in pregnancy, so LMWH is the anticoagulant of choice.

Swallow dabigatran capsules whole — never break, chew or open them — and expect dyspepsia, its most common nonbleeding adverse effect.

Neuraxial anesthesia on LMWH carries a boxed warning for spinal or epidural hematoma; time catheter placement and removal around doses (see the VTE Prophylaxis sheet).

Pearl

CrCl under 30 mL/min: reach for IV unfractionated heparin — not renally cleared, titratable and fully reversible with protamine.